At the Consensus Development Conference sponsored by The National Institutes of Health (NIH) in 2000, the definition of osteoporosis was proposed as follows: “A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.” In fact, osteoporosis is perceived as a disease of compromised bone strength due to decreased bone density and deteriorated bone quality (Non Patent Document 1). Osteoporosis is classified into primary osteoporosis and secondary osteoporosis, where the former involves compromised bone density associated with ageing, menopause, and pregnancy, while the latter is caused by some kind of disease as an underlying cause.
Compromised bone density is caused when accelerated bone resorption outpaces bone formation, and is also associated with reduced osteoblast function and associated reduced bone formation (Non Patent Document 2). That is, predominant bone resorption resulting from an imbalance in bone remodeling via bone resorption and bone formation is closely associated with pathology.
At present, in Japan, the number of patients in need of treatment of osteoporosis is assumed to be 12.80 million (2005), including the total of lumbar vertebrae and femoral neck. The number of femoral neck fracture events is rapidly increasing, with the number of patients reaching 148,100 per year. In light of the above, various therapeutic methods and preventive agents are being developed.
Currently, as therapeutic agents for osteoporosis, calcium absorption-promoting drugs, bone formation-promoting drugs, and bone resorption-inhibiting drugs are primarily used. While these therapeutic agents show efficacy, however, serious adverse reactions have been reported. For example, the most frequent adverse reaction to calcium preparations is gastrointestinal disorder. When activated vitamin D3 preparations are concomitantly used, regular blood testing is necessary due to potential hypercalcemia (Non Patent Document 3).
As major adverse reactions to bisphosphonate preparations, for example, gastrointestinal disorder, osteonecrosis of jaw, atypical femur fracture, hypocalcaemia, renal disorder and influenza-like symptoms have been reported (Non Patent Document 4). Moreover, the half-life of bisphosphonate is long, and it may remain in the skeleton for several years even after discontinuation of treatment. Excessive long-term inhibition of bone remodeling may cause unfavorable effects such as brittle bone caused by increased bone mineralization as well as increased microdamage.
Further, for postmenopausal bone mass loss, estrogen preparations, and selective estrogen receptor modulators (SERM), which act on the estrogen receptors on bone more selectively than estrogen preparations, are used. However, for estrogen preparations, not only adverse reactions peculiar to female hormones such as endometrial bleeding, increased vaginal discharge, and breast pain, but also deep vein thromboembolism and increased risk of developing breast cancer and endometrial cancer have been reported (Non Patent Document 5). Further, as to SERM, while adverse reactions affecting the breasts and uterine were successfully inhibited, deep vein thromboembolism, hot flash, and leg cramp are still reported (Non Patent Document 6).
In view of the above, clinical development has recently been taking place for therapeutic agents for osteoporosis aiming at new targets, such as cathepsin K inhibitors, Src kinase inhibitors, and anti-sclerostin antibodies (Non Patent Documents 7, 8, and 9). Nevertheless, the current situation is that no therapeutic drug for osteoporosis which satisfies both excellent efficacy and safety has yet been available.
Meanwhile, acyl thiourea compounds having an aminocarbonyl group at the 6-position and an alkoxy group at the 7-position in the quinolone ring such as 4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamide are known to be an antitumor agent showing a potent inhibitory effect on c-Met and inhibition of VEGF receptors with reduced adverse reactions (Patent Document 1). It is also known that when such a compound is used concomitantly with other antitumor agents, it exhibits an excellent antitumor effect-enhancing action (Patent Document 2).
Nevertheless, this compound is totally unknown to be effective for osteoporosis.